SUMMARY Tobacco is highly addictive and despite increasing awareness about the adverse health effects of smoking each day thousands of adolescents start experimenting with cigarettes. About two-thirds of them transition from occasional to daily smoking and develop a nicotine addiction. The long-term goal of this research program is to determine if decreasing the nicotine content in tobacco will prevent the transition to daily smoking and the development of nicotine addiction in adolescents. Decreasing the nicotine content in tobacco has been proposed as an alternative approach to reduce smoking. Indeed, clinical studies indicate that adults with a nicotine addiction smoke fewer low-nicotine cigarettes than conventional high-nicotine cigarettes. It is, however, not known if adolescents are less likely to develop a nicotine addiction when they smoke low-nicotine cigarettes. For ethical reasons it is not possible to compare the reinforcing properties of low and high-nicotine cigarettes in adolescents. The objective of our studies is to determine if the positive and negative reinforcing properties of low-nicotine cigarettes are diminished compared to those of high-nicotine cigarettes. The positive reinforcing effects of nicotine are critical for the initiation of smoking and the negative reinforcing effects of withdrawal prevent people from maintaining abstinence. We will use an established rat tobacco-smoke exposure procedure to investigate the reinforcing properties of low, intermediate, and high-nicotine cigarettes. Based on our previous nicotine and tobacco smoke exposure studies, it is hypothesized that there is a positive relationship between the nicotine-content of tobacco and the reinforcing properties of cigarettes. Three aims are proposed to test this hypothesis. 1) Determine if the nicotine content of tobacco affects the rewarding properties of smoke in adolescent male and female rats. Adolescent rats will be used to study the rewarding effects of tobacco smoke because people start smoking during adolescence and this is a period of enhanced vulnerability for developing a nicotine addiction. 2) Determine if exposure to tobacco smoke with various nicotine levels during early- to mid-adolescence affects the acquisition of nicotine intake and the motivation to self- administer nicotine during late adolescence in male and female rats. 3) Determine if the nicotine content of tobacco affects the development of nicotine dependence during adolescence and early adulthood in males and females. People start smoking during adolescence and attempt to quit smoking during young adulthood. Therefore, withdrawal will be investigated in young adult rats in which smoke exposure was initiated during adolescence. It is predicted that lowering the nicotine content in tobacco will decrease the positive and negative reinforcing properties of cigarettes. Consequently, lowering the nicotine content in tobacco would decrease the burden of cigarettes on society as fewer adolescents transition to daily smoking and develop a nicotine addiction. These studies will inform the FDA?s regulatory authority about the effectiveness of reducing the nicotine content in tobacco as a measure to prevent the transition to daily smoking and nicotine addiction.